Nutrition & Metabolism

This Provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted
PDF and full text (HTML) versions will be made available soon.

DHEA administration and exercise training improves insulin resistance in obese

rats
Nutrition & Metabolism 2012, 9:47 doi:10.1186/1743-7075-9-47

Koji Sato (sato712@fc.ritsumei.ac.jp)

Motoyuki Iemitsu (iemitsu@fc.ritsumei.ac.jp)
Katsuji Aizawa (katsuji.aizawa@gmail.com)
Noboru Mesaki (mesaki@thu.ac.jp)
Ryuichi Ajisaka (sajisaka@taiiku.tsukuba.ac.jp)
Satoshi Fujita (safujita@fc.ritsumei.ac.jp)

ISSN 1743-7075

Article type Research

Submission date 28 October 2011

Acceptance date 2 March 2012

Publication date 30 May 2012

Article URL http://www.nutritionandmetabolism.com/content/9/1/47

This peer-reviewed article was published immediately upon acceptance. It can be downloaded,
printed and distributed freely for any purposes (see copyright notice below).

Articles in Nutrition & Metabolism are listed in PubMed and archived at PubMed Central.

For information about publishing your research in Nutrition & Metabolism or any BioMed Central
journal, go to

http://www.nutritionandmetabolism.com/authors/instructions/

For information about other BioMed Central publications go to

http://www.biomedcentral.com/

© 2012 Sato et al. ; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
DHEA administration and exercise training
improves insulin resistance in obese rats
Koji Sato1
Email: sato712@fc.ritsumei.ac.jp

Motoyuki Iemitsu1
Email: iemitsu@fc.ritsumei.ac.jp

Katsuji Aizawa2
Email: katsuji.aizawa@gmail.com

Noboru Mesaki3
Email: mesaki@thu.ac.jp

Ryuichi Ajisaka4
Email: sajisaka@taiiku.tsukuba.ac.jp

Satoshi Fujita1*
*
Corresponding author
Email: safujita@fc.ritsumei.ac.jp
1
Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga,
Japan
2
Department of literature, Senshu University, Kawasaki, Kanagawa, Japan
3
University of Tsukuba, Tsukuba, Ibaraki, Japan
4
Department of Comprehensive Human Sciences, University of Tsukuba,
Tsukuba, Ibaraki, Japan

Abstract
Background

Dehydroepiandrosterone (DHEA) is precursor of sex steroid hormone. We demonstrated that

acute DHEA injection to type 1 diabetes model rats induced improvement of hyperglycemia.
However, the effect of the combination of DHEA administration and exercise training on
insulin resistance is still unclear. This study was undertaken to determine whether 6-weeks of
DHEA administration and/or exercise training improve insulin resistance in obese male rats.

Methods

After 14 weeks of a high-sucrose diet, obese male Wistar rats were assigned randomly to one
of four groups: control, DHEA administration, exercise training, and a combination of DHEA
administration and exercise training (n = 10 each group).
Results

After 6-weeks of DHEA administration and/or exercise training, rats in the combination
group weighed significantly less and had lower serum insulin levels than rats in the other
groups. Moreover, the rats treated with DHEA alone or DHEA and exercise had significantly
lower fasting glucose levels (combination, 84 ± 6.5 mg/dL; DHEA, 102 ± 9.5 mg/dL; control,
148 ± 10.5 mg/dL). In addition, insulin sensitivity check index showed significant
improvements in the combination group (combination, 0.347 ± 0.11; exercise, 0.337 ± 0.16%;
DHEA, 0.331 ± 0.14; control, 0.308 ± 0.12). Muscular DHEA and 5α-dihydrotestosterone
(DHT) concentrations were significantly higher in the combination group, and closely
correlated with the quantitative insulin-sensitivity check index (DHEA: r = 0.71, p < 0.01;
DHT: r = 0.69, p < 0.01).

Conclusion

These results showed that a combination of DHEA administration and exercise training
effectively improved fasting blood glucose and insulin levels, and insulin sensitivity, which
may reflect increased muscular DHEA and DHT concentrations.

Keywords
Exercise training, Insulin sensitivity, Sex steroid hormone, Obesity

Introduction
Obesity is one of the risk factors for type 2 diabetes, cardiovascular diseases, hypertension,
and dyslipidemia. The obesity and type 2 diabetes patients show lower concentrations of
dehydroepiandrosterone (DHEA) and other sex steroid hormone [1-3]. Decreased DHEA
levels in obese patients or those with type 2 diabetes are related to insulin-induced inhibition
of enzyme activity for adrenal androgen synthesis [4]. However, DHEA administration and
exercise leads to increases in muscular steroidogenesis-related enzymes and concomitant
increases in plasma and muscular DHEA and 5α-dihydrotestosterone (DHT) levels in rats [5-
7]. Moreover, several reports demonstrated that short-term (2 weeks) DHEA administration
induced an acute decrease in blood glucose levels in mice [8,9], reduced serum insulin levels
in older rats [2,10,11], and enhanced the activities of enzyme related to hepatic glucose
metabolismin diet-induced or Zucker obese rats [12,13]. Recently, we have reported that
acute DHEA injections improved hyperglycemia in streptozotocin (STZ)-induced diabetic
rats [7]. In addition, Han and colleagues [14] demonstrated an enhanced insulin sensitivity in
response to 2 weeks of wheel-running exercise and DHEA administration in 25-month-old
rats, although additive effects of the treatments were not apparent.

DHEA and its sulfate derivate (DHEA-S) are precursors of sex steroid hormones, that
circulate in blood before they are used by target tissues. Generally, DHEA is produced by
adrenal, but several studies demonstrated that brain, liver, bone and any other tissues can also
produce DHEA in both human and rodents [15-17]. Recently, we demonstrated that skeletal
muscle can locally synthesize DHT from DHEA and testosterone [18]. According to our
previous studies, acute aerobic exercise enhances the local bioactive androgen metabolism,
and increased DHEA and DHT levels in skeletal muscle (5. 6). It is still unclear whether the
combination of chronic DHEA administration and aerobic exercise training increases
muscular level of DHEA and DHT, and it induces the improvement of insulin resistance
more effectively in obesity.

We hypothesized that, compared with either DHEA administration or exercise training

treatment alone, 6-weeks of DHEA administration combined with exercise training in obese
rats would produce larger effects on steroidogenesis from DHEA to DHT in skeletal muscle
and improvements in insulin sensitivity. To test this hypothesis, we investigated fasting blood
glucose, insulin levels, the quantitative insulin-sensitivity check index (QUICKI) as an index
of insulin sensitivity after 6-weeks of DHEA administration, exercise training, or both in rats
with diet-induced obesity.

Methods
Ethical approval for this study was obtained from the Committee on Animal Care at the
University of Tsukuba. Male Wistar rats (220–250 g, 10 weeks old; Charles River Japan,
Kanagawa, Japan) were cared for according to The Guiding Principles for the Care and Use
of Animals based on the Declaration of Helsinki. The Wistar rats were housed individually in
an animal facility under controlled conditions (12:12-h light–dark cycle). The rats were
allowed water ad libitum and placed on a purified high-sucrose diet (68% of kcal from
sucrose, 20% from protein, and 12% from fat) for 14 weeks, according to a previous study
with minor modifications [19]. After 14 weeks of the high-sucrose diet, the animals were
randomly assigned to one of four groups: sedentary rats administered sesame oil (control
group, n = 10), obese rats treated with DHEA (DHEA group, n = 10), obese rats subjected to
exercise training (exercise group, n = 10), and obese rats treated with DHEA and subjected to
exercise training (combination group, n = 10). DHEA was obtained from Wako Pure
Chemical Industries (Osaka, Japan). All animals continued on the high-sucrose diet during
the 6-week experimental period. In the DHEA and combination groups, DHEA (1 mg/kg
body weight) dissolved in sesame oil was administered orally every day for 6 weeks. In the
control group, the same amount of vehicle (sesame oil) was administered orally every day.
Body weight and dietary intake were measured every week during the experiment. Post-
training experiments in trained rats were performed 48 h after the last round of exercise
training. After all other measurements were obtained the soleus and gastrocnemius muscles
were quickly removed, weighed, rinsed in ice-cold saline, and frozen in liquid nitrogen.

Exercise protocol

The obese exercise training group was trained on a rodent treadmill (KN-73, Natsume
Seisakusyo, Tokyo, Japan) at about 10–25 m/min over a period of 3 days for accustomed to
the treadmill. The rats then ran on the treadmill for 1 h at 25 m/min without incline 5
days/week for 6 weeks. The intensity, duration and time of the exercise was kept constant
during the rest of the training period.

Protein assay and muscle concentrations of DHEA and DHT

Muscle specimens were homogenized in 20 mM Tris–HCl (pH 7.8), 300 mM NaCl, 2 mM

ethylenediaminetetraacetic acid (EDTA), 2 mM dithiothreitol (DTT), 2% nonident P-40,
0.2% sodium lauryl sulphate (SDS), 0.2% sodium deoxycholate, 0.5 mM
phenylmethylsulfonyl fluoride, 60µg/ml aprotinin, and 1 µg/ml leupeptin. Homogenates were
rotated slowly for 30 min at 4°C and then centrifuged at 12,000 × g for 15 min at 4°C. The
protein concentration of the resulting supernatant was determined. For the determination of
DHEA and DHT levels, muscle samples were diluted by 200 times with each assay buffer.
The levels of DHEA and DHT in skeletal muscle extracts were determined using Enzyme-
Linked Immuno Sorbent Assay (ELISA) kit (Assay Designs, Ann Arbor, MI, IBL Hamburg,
Germany). The techniques and materials used in these analyses followed the manufacturer’s
protocol. The immobilized polyclonal antibodies were raised against DHEA and DHT,
whereas the secondary horseradish-peroxidase-coupled antibodies were monoclonal. Optical
density at 450 nm was measured on a microplate reader (BioLumin 960; Molecular
Dynamics, Tokyo, Japan). All samples were assayed in duplicate.

Glucose and insulin concentrations

Serum insulin concentrations were measured using an ELISA kit (Shibayagi Co, Gunma,
Japan), according to the manufacturer’s protocol. All samples were assayed in duplicate.
Optical density at 450 nm was qualified using a microplate reader (BioLumin 960; Molecular
Dynamics, Tokyo, Japan). Fasting glucose was assessed from the tail vein before and after
the treatment period under overnight fasting condition. Glucose concentrations were assessed
three times from the tail vein using a blood glucose meter (Ascensia, Bayer HealthCare,
Tokyo, Japan).

Insulin sensitivity

QUICKI was calculated according to the previous study from fasting glucose and insulin
values [20-22]. QUICKI = 1/[log (I0) + log (G0)], where I0 is fasting insulin (µU/ml), and G0
is fasting glucose (mg/dl).

Statistical analysis

All values are expressed as means ± SE. Statistical evaluations were performed using
repeated measures two-way ANOVA (time × group) for weight changes. A post-hoc
comparison test was used to correct for multiple comparisons (Bonferroni test) when analyses
revealed significant differences. For ANOVA, P < 0.01 was considered significant.
Relationships between sex steroid hormone concentrations and the quantitative insulin-
sensitivity check index (QUICKI) was determined using Pearson correlation coefficients.

Results
Body weight

Body weight before the treatment periods did not differ among the groups. After 6 weeks of
DHEA administration and/or exercise training, body weight was significantly (p < 0.01)
lower in the combination group than in the control group. After 5 weeks, body weight was
significantly (p < 0.01) lower in the combination group than in the DHEA group or the
exercise group (Figure 1). Final body weights in the DHEA and exercise groups were
significantly lower than in the control group. Moreover, the combination group showed a
significantly lower body weight than the other groups (Figure 1).
Figure 1 Body weight before and after dehydroepiandrosterone (DHEA) treatment and
exercise training in obese rats fed a high-sucrose diet. Diamonds: Control group.
Circles:DHEA treatment group. Squares: Exercise training group. Triangles: Combination
group Data are means ± SE from 10 animals. Pre: before DHEA treatment and/or exercise
training. The x axis represents the weeks of DHEA treatment and/or exercise training. * p <
0.01 compared with the control group. †p < 0.01 compared with the DHEA group. ‡ p < 0.01
compared with the exercise training group

Dietary intake, muscle weight and epididymal fat weight

Exercise training and DHEA administration did not decrease food intake of the rats. Average
food intake during the 6 weeks was 19.74 ± 0.62 g/day in the control group, 19.64 ± 0.37
g/day in the DHEA group, 19.61 ± 0.43 g/day in the exercise group, and 19.59 ± 0.53 g/day in
the combination group. No significant difference in the food intake was found among groups
during the treatment period (Table 1).

Table 1 Animal characteristics

Sedentary DHEA Training Training-DHEA
(n = 10) (n = 10) (n = 10) (n = 10)
Muscle weight (g/body weight)
Soleus 0.32 ± 0.02 0.48 ± 0.04 * 0.56 ± 0.03 *† 0.57 ± 0.04 *†
Gastrocnemius 3.63 ± 0.6 4.31 ± 0.3 * 4.66 ± 0.3 *† 4.73 ± 0.3 *†
Epididymal fat (g) 38.2 ± 4.8 27.4 ± 3.6 * 33.8 ± 2.8 23.7 ± 4.1 *‡
Dietary intake(g/day) 19.74 ± 0.62 19.64 ± 0.37 19.61 ± 0.43 19.59 ± 0.53
Pre-fasting glucose(mg/dl) 154 ± 11.5 159 ± 10.2 162 ± 8.7 158 ± 9.8
Post-fasting glucose(mg/dl) 148 ± 10.5 102 ± 9.5 * 92 ± 7.8 * 84 ± 6.5 *†
DHEA:dehydroepiandrosterone
Pre-fasting glucose: fasting glucose level before DHEA administration and/or exercise
training
Post-fasting glucose: fasting glucose level after DHEA administration and/or exercise
training
Data are means ± SE
* P < 0,05, vs Sedentary control group
†P < 0.05, vs DHEA treatment group
‡P < 0.05, vs Training group

Table 1 shows the weights of the soleus and gastrocnemius muscles after the treatment
period. Marked increases in the weight of the soleus and gastrocnemius muscles were
observed in the exercise and combination groups compared with the control and DHEA
groups. The soleus and gastrocnemius muscles weighed significantly more in the DHEA
group than in the control group (p < 0.01, Table 1). Epididymal fat weight was significantly
decreased in combination group compared to control and exercise group (p < 0.01, Table 1).

Fasting glucose levels, serum insulin levels, and QUICKI

The fasting glucose levels were not significantly different among groups before the treatment
periods (Table 1). After 6 weeks of DHEA administration and/or exercise training, fasting
glucose levels were significantly lower in the DHEA, exercise, and combination groups than
in the control group. Moreover, fasting glucose levels in the combination group were
significantly lower than in the DHEA group (Table 1).

After 6 weeks of DHEA administration and/or exercise training, the serum insulin levels were
significantly lower in the DHEA, exercise, and combination groups than in the control group.
Serum insulin levels were also significantly lower in the combination group than in the other
groups (Figure 2A). Similarly, QUICKI were significantly higher in the DHEA, exercise, and
the combination groups than in the control group (p < 0.01. Figure 2B). Of particular interest,
the QUICKI were significantly higher in the combination group than in the other groups (p <
0.01). No significant correlation between body weight and fasting glucose, or body weight
and QUICKI was found in the present study.

Figure 2 Effects of DHEA treatment and/or exercise training on serum insulin levels (A)
and the QUICKI (B). Data are the means ± SE from 10 animals. * p < 0.01 compared with
the control group. †p < 0.01 compared with the DHEA group. ‡ p < 0.01 compared with the
exercise training group

Intramuscular DHEA and DHT concentrations

Intramuscular DHEA and DHT concentrations were significantly greater in the DHEA,
exercise, and combination groups than in the control group. The DHEA and DHT
concentrations were also significantly greater in the combination group than in either the
DHEA or exercise group (Figure 3A and 3B). Of note, intramuscular DHEA and DHT
concentrations significantly correlated with QUICKI (DHEA: r = 0.71, p < 0.001; DHT: r =
0.69, p < 0.001. Figure 4).

Figure 3 Effects of DHEA treatment and/or exercise training on muscle DHEA and 5α-
dihydrotestosterone (DHT) concentrations. Data are means ± SE from 10 animals. *p <
0.01 compared with the control group. †p < 0.01 compared with the DHEA group. ‡ p < 0.01
compared with the exercise training group

Figure 4 Correlations between muscular DHEA and the QUICKI (A) and muscular
DHT and the QUICKI (B) in combination treatment groups

Discussion
Results from this study demonstrated that 6-weeks of DHEA treatment with exercise training
induced larger decreases in fasting glucose levels than results observed for DHEA
administration alone. The combined interventions were more beneficial for insulin resistance
and body weight than either DHEA administration or exercise training alone. These effects in
the combination group may have reflected significant increases in muscular DHEA and DHT
levels, which closely correlated with QUICKI.

In the present study, both exercise training and DHEA administration significantly increased
muscular concentrations of DHEA and DHT, and these increases were even more
pronounced when these treatment modalities were combined. In fact, muscular DHEA and
DHT concentrations significantly correlated with QUICKI in this study. Recently, a single
DHEA injection in rats with STZ-induced diabetes was shown to reverse impaired GLUT-4-
related signaling in muscle, such as Akt/PKCζ/λ activity and GLUT-4 translocation [7].
Additionally, short-term exercise training is known to improve blood glucose levels and
accelerate muscular glucose uptake and utilization [23]. Therefore, the combination of DHEA
administration and exercise training may additively or synergistically improve blood glucose
levels and activate the glucose uptake in skeletal muscle. According to Han et al. [14], plasma
insulin levels decreased and the glucose infusion rate was increased by DHEA treatment and
voluntary running-wheel training in 25-month-old rats. Additive effects were not observed in
the combination group, however. In the present study, a 6-week regimen of DHEA
administration and exercise training resulted in larger improvements in hyperglycemia and
insulin resistance in the obese rats. Consequently, a longer treatment period, such as the 6-
week regimen used in this study, may be required to obtain additive benefits for improvement
of insulin sensitivity in diet-induced obese rats.

Although DHEA administration and exercise training each produced beneficial effects, 6-
weeks of combination treatment were more effective for obesity. The precise mechanisms
that reduced abdominal fat weight in the combination group remain unclear, yet we can
propose several plausible hypotheses. 2 weeks of DHEA administration has been shown to
activate fatty acid metabolism-related enzymes, such as long-chain fatty acyl-coenzyme A
synthase, and to increase free CoA levels in liver [12,13]. In addition, exercise training is
known to reduce adipogenesis via upregulation of fatty acid metabolism and increased energy
expenditure [24]. Therefore, 6-weeks of combination treatment may have promoted additive
reductions in abdominal fat volume.

Patients with metabolic syndrome have lower DHEA and DHEA-S levels [25]. We recently
demonstrated that DHEA enhanced GLUT-4-relatedsignaling in cultured skeletal muscle
cells [18]. Furthermore, rats with STZ-induced diabetes had lower muscle DHEA
concentrations, and acute DHEA injections improved GLUT-4-relatedsignaling with
increased muscular DHEA and DHT levels. Therefore, muscular DHEA and DHT levels
appear to be related to blood glucose levels in obesity and type 2 diabetes. The present study
showed that DHEA administration, exercise training, and combination of the two modalities
significantly increased basal muscular DHEA and DHT levels. Moreover, brief exercise
significantly increases muscular levels of DHEA and steroidogenesis-related enzymes [5,6].
Exercise training is beneficial for patients with insulin resistance and hyperinsulinemia
[26,27]. Although exercise training has been shown to improve insulin resistance and glucose
metabolism in obese patients with type 2 diabetes, most effects are observed after longer
exercise programs. Therefore, combination treatment may be more beneficial than either
therapy alone. Increasing basal muscular DHEA and DHT levels with DHEA and regular
exercise may provide additive benefits for reducing abdominal fat weight and improving
insulin resistance in obesity. However, the present study was conducted with relatively small
number of experiments; therefore, further studies are warranted to confirm the current
findings and to clarify the molecular mechanisms for combined benefits of DHEA and
exercise training.

Although this combined treatment modalities may provide a new therapeutic avenue for
obesity and insulin resistance related to obesity, previous studies have reported some mixed
results. While one study indicated that DHEA administration improved insulin sensitivity in
elderly people [28,29], others demonstrated no improvement in insulin sensitivity or body
composition [30]. Therefore, further studies are necessary to clarify the effect of DHEA
supplementation not only in healthy adults but also in obese or diabetic patients.
In conclusion, the results from this study demonstrated that 6-weeks of DHEA administration
combined with exercise training produced larger benefits for insulin sensitivity, body weight,
and abdominal fat compared with DHEA administration or exercise training alone.

Abbreviations
DHEA, Dehydroepiandrosterone; DHEA-S, DHEA sulfate; DHT, 5α-dihydrotestosterone;
QUICKI, Quantitative insulin-sensitivity check index.

Competing interests
The authors declare that they have no competing interests.

Authors’ contribution
SK: AB, IM:ES, AK: ES, MN: ES, AR: FG, FS: FG. All authors read and approved the final
manuscript.

Acknowledgement
This work was supported by grants-in-aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology of Japan (23700849, 21300254,
22650166). This work was funded by a Sasakawa Scientific Research Grant from The Japan
Science Society (24-445).

References
1. Berdanier CD, Parente JA Jr, McIntosh MK: Is dehydroepiandrosterone an antiobesity
agent? FASEB J 1993, 7:414–419.

2. Cleary MP, Zisk JF: Anti-obesity effect of two different levels of

dehydroepiandrosterone in lean and obese middle-aged female Zucker rats. Int J Obes
1986, 10:193–204.

3. Lea-Currie YR, Wen P, McIntosh MK: Dehydroepiandrosterone-sulfate (DHEAS)

reduces adipocyte hyperplasia associated with feeding rats a high-fat diet. Int J
ObesRelatMetabDisord 1997, 21:1058–1064.

4. Kapoor D, Malkin CJ, Channer KS, Jones TH: Androgens, insulin resistance and
vascular disease in men. Clinical Endocrinology 2005, 63:239–250.

5. Aizawa K, Iemitsu M, Otsuki T, Maeda S, Miyauchi T, Mesaki N: Sex differences in

steroidogenesis in skeletal muscle following a single bout of exercise in rats. J Appl
Physiol 2008, 104:67–74.
6. Aizawa K, Iemitsu M, Maeda S, Otsuki T, Sato K, Ushida T, Mesaki N, Akimoto T:
Acute exercise activates local bioactive androgen metabolism in skeletal muscle. Steroids
2010, 75:219–223.

7. Sato K, Iemitsu M, Aizawa K, Ajisaka R: DHEA improves impaired activation of Akt

and PKC ζ/λ-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in
streptozotocin-induced diabetes rats. Acta Physiol 2009, 197:217–225.

8. Coleman DL, Leiter EH, Schwizer RW: Therapeutic effects of dehydroepiandrosterone

(DHEA) in diabetic mice. Diabetes 1982, 31:830–833.

9. Coleman DL, Schwizer RW, Leiter EH: Effect of genetic background on the
therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and
in aged normal mice. Diabetes 1984, 33:26–32.

10. Cleary MP, Shephard A, Zisk J, Schwartz A: Effect of dehydroepiandrosterone on

body weight and food intake in rats. NutrBehav 1983, 1:127–136.

11. Tagliaferro AR, Ronan AM, Payne J, Meeker LD, Tse S: Increased lipolysis to beta-
adrenergic stimulation after dehydroepiandrosterone treatment in rats. Am J Physiol
1995, 268:R1374–R1380.

12. Mohan PF, Cleary MP: Effect of short-term DHEA administration on liver
metabolism of lean and obese rats. Am J Physiol 1988, 255:E2–E8.

13. Mohan PF, Ihnen JS, Levin BE, Cleary MP: Effects of dehydroepiandrosterone
treatment in rats with diet-induced obesity. J Nutr 1990, 120:1103–1114.

14. Han DH, Hansen PA, Chen MM: Holloszy JO.DHEA treatment reduces fat
accumulation and protects against insulin resistance in male rats.J Gerontol A BiolSci.
Med Sci 1998, 53:19–24.

15. Grasfeder LL, Gaillard S, Hammes SR, Ilkayeva O, Newgard CB, Hochberg RB, Dwyer
MA, Chang CY, McDonnell DP: Fasting-induced hepatic production of DHEA is
regulated by PGC-1[alpha], ERR[alpha], and HNF4 [alpha]. Mol Endocrinol 2009,
23:1171–1182.

16. Mellon SH, Griffin LD, Compagnone NA: Biosynthesis and action of neurosteroids.
Brain Res Rev 2001, 37:3–12.

17. Takeuchi S, Mukai N, Tateishi T, Miyakawa S: Production of sex steroid hormones

from DHEA in articular chondrocyte of rats. Am J Physiol 2007, 293:E410–E415.

18. Sato K, Iemitsu M, Aizawa K, Ajisaka R: Testosterone and DHEA activate the
glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol 2008,
294:E961–E968.

19. Commerford SR, Ferniza JB, Bizeau ME, Thresher JS, Willis WT, Pagliassotti MJ: Diets
enriched in sucrose or fat increase gluconeogenesis and G-6-Pase but not basal glucose
production in rats. Am J Physiol 2002, 283:E545–E555.
20. Levy JR, Clore JN, Stevens W: Dietary n-3 polyunsaturated fatty acids decrease
hepatic triglycerides in Fischer 344 rats. Hepatology 2004, 39:608–616.

21. Chen H, Sullivan G, Yue LQ, Katz A, Quon MJ: QUICKI is a useful index of insulin
sensitivity in subjects with hypertension. Am J Physiol 2003, 4:E804–E812.

22. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ:
Quantitative insulin sensitivity check index: a simple, accurate method for assessing
insulin sensitivity in humans. J clin Endocrinol Metab 2000, 85:2402–2410.

23. Jessen N, Pold R, Buhl ES, Jensen LS, Schmitz O, Lund S: Effects of AICAR and
exercise on insulin-stimulated glucose uptake, signalling, and GLUT4 content in rat
muscles. J Appl Physiol 2003, 94:1373–1379.

24. Hou CW, Chou SW, Ho HY, Lee WC, Lin CH, Kuo CH: Interactive effect of exercise
training and growth hormone administration on glucose tolerance and muscle GLUT4
protein expression in rats. J Biomed Sci 2003, 10:689–696.

25. Yamaguchi Y, Tanaka S, Yamakawa T, Kimura M, Ukawa K, Yamada Y, Ishihara M,

Sekihara H: Reduced serum dehydroepiandrosterone levels in diabetic patients with
hyperinsulinaemia. Clin Endocrinol 1998, 49:377–383.

26. Ivy JL, Young JC, Craig BW, Kohrt WM, Holloszy JO: Ageing, exercise and food
restriction: effects on skeletal glucose uptake. Mech Ageing Dev 1991, 61:123–133.

27. Sanchez J, Heredia FP, Priego T, Portillo MP, Zamora S, Garaulet M, Palou A:
Dehydroepiandrosterone prevents age-associated alterations, increasing insulin
sensitivity. J Nutr Biochem 2008, 19:809–818.

28. Jedrzejuk D, Medras M, Milewicz A, Demissie M: Dehydroepiandrosterone

replacement in health men with age-related decline of DHEA-S: effects of fat
distribution, insulin sensitivity and lipid metabolism. Aging male 2003, 6:151–156.

29. Villareal DT, Hollszy JO: Effect of DHEA on abdominal fat and insulin action in
elderly women and men. JAMA 2004, 292:2243–2248.

30. Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG,
Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton LJ 3rd, Smith GE,
Khosla S, Jensen MD: DHEA in elderly women and DHEA or testosterone in elderly
men. N Engl J Med 2006, 355:1647–1659.
Figure 1
Figure 2
Figure 3
Figure 4